Professional Documents
Culture Documents
Autoimmune hemolytic anemia is a hetero- nectomy can be regarded as the most effec- autoimmune hemolytic anemias respond
geneous disease with respect to the type of tive and best-evaluated second-line therapy, well to rituximab but are resistant to ste-
the antibody involved and the absence or but there are still only limited data on long- roids and splenectomy. The most common
Introduction
Autoimmune hemolytic anemia (AIHA) is a rare disease. In a is required. For the diagnosis of secondary AIHA a careful history,
recent population-based study1 the incidence was 0.8/100 000/year, including information on the onset (acute or insidious), history of
but the prevalence is 17/100 000.2 Primary (idiopathic) AIHA is infections, information on recent transfusions, exposure to drugs or
less frequent than secondary AIHA. Secondary cases are often vaccination, signs of immune disease (arthritis), and general
challenging because not only AIHA but also the underlying clinical condition are helpful. The exclusion of a drug-induced
disease(s) must be diagnosed and treated. AIHA is essentially hemolytic anemia is particularly important, because stopping the
diagnosed in the laboratory, and considerable improvement has drug is the most effective therapeutic measure in this situation. A
been made in this field. However, progress in treatment has been clinical examination (to rule out lymphadenopathy, splenomegaly)
much slower.3-8 Therapy has been reviewed by several investiga- is obligatory. The need for additional investigations must be
tors,8-15 but no treatment guidelines have yet been published. determined by history, clinical findings, and the type of antibody.
Routine work-up relevant for treatment decisions may include
abdominal examination by computed tomographic scan (to search
Diagnosis for splenomegaly, abdominal lymphomas, ovarian dermoid cysts,
renal cell carcinoma), quantitative determination of immunoglobu-
The diagnosis of AIHA is usually straightforward and made on the lins, a search for a lupus anticoagulant in case of warm antibodies,
basis of the following laboratory findings: normocytic or macro- or a bone marrow examination and a search for clonal immunoglobu-
cytic anemia, reticulocytosis, low serum haptoglobin levels, el- lins (immune fixation) in case of cold antibodies.
evated lactate dehydrogenase (LDH) level, increased indirect The list of underlying diseases in which AIHA can occur is long. The
bilirubin level, and a positive direct antiglobulin test with a most common underlying diseases are lymphoproliferative disorders
broad-spectrum antibody against immunoglobulin and complement and immune diseases. Among others, the type of AIHA is the most
(Figure 1). However, there are pitfalls, particularly in secondary important clue to the most likely underlying disease (Table 1).
cases, because not always are all of the typical laboratory findings
of AIHA present.15 Two pieces of information are of utmost
importance for the clinician to make an appropriate treatment
decision: (1) What type of the antibody is involved? (2) Is the Treatment of AIHA
AIHA primary or secondary? The type of antibody can be identified General remarks
with the use of monospecific antibodies to immunoglobulin G
(IgG) and C3d. When the red cells are coated with IgG or IgG plus This review deals only with the treatment of adult AIHA.
C3d, the antibody is usually a warm antibody (warm antibody In the era of evidence-based medicine it is surprising and
AIHA [WAIHA]). When the red cells are coated with C3d only, the regrettable that treatment of AIHA is still not evidence-based, but
antibody is often but not always a cold antibody. For definite essentially experience-based. There are no randomized studies and
diagnosis of a cold antibody AIHA (CAIHA), the cold agglutinin only a few prospective phase 2 trials. Otherwise, only retrospective
titer should be markedly elevated (⬎ 1:512). In some cases (direct studies, small series of (probably selected) patients or single cases
antiglobulin test negativity, IgM warm antibodies, cold antibodies have been reported (evidence level V). There is no formal
with low titers, or Donath-Landsteiner antibodies), diagnosis may consensus on the definition of complete (CR) or partial (PR)
be difficult, and the expertise of an immune-hematologic laboratory hematologic remission and refractoriness. We found more than
Submitted March 29, 2010; accepted May 21, 2010. Prepublished online as © 2010 by The American Society of Hematology
Blood First Edition paper, June 14, 2010; DOI 10.1182/blood-2010-03-259325.
NHL indicates non-Hodgkin lymphoma; SLE, systemic lupus erythematosus; CVID, common variable immune deficiency; ALPD, autoimmune lymphoproliferative disease;
and SCT, stem cell transplantation.
*Data from recent and/or larger studies.
BLOOD, 16 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 11 AUTOIMMUNE HEMOLYTIC ANEMIAS IN ADULTS 1833
ward: rapid infusion of 20 mL of blood, 20 minutes’ observation, Patients who are refractory to initial steroid therapy are easily
and, if there is no reaction, further transfusion at the usual speed. In convinced of the need for a second-line therapy, because they
critical cases transfusions should not be avoided or delayed usually have severe side effects of steroid therapy. Patients of the
because of uncertainty in matching. Even a small amount of second category are often subjectively satisfied with corticosteroid
transfused blood can be life-saving. The value of plasmapheresis to therapy and often want to proceed with this treatment. However,
reduce antibody titers is unproven.34 In WAIHA treatment with they are usually not aware of the risks of long-term corticosteroid
steroids should begin immediately. In patients with CAIHA treatment. They probably hope for a late remission that may occur
transfused blood must be prewarmed with the use of commercial but is not very likely (in contrast to autoimmune thrombocytopenia).
warming coils. If the decision for a second-line treatment has been made, there
are several options. For each option the benefit/risk ratio should be
Treatment of (primary) idiopathic WAIHA
individually assessed.
Table 2. Suggested sequence of treatments in primary and secondary WAIHA and CAIHA
Disease or condition First line Second line Beyond second line Last resort References
Primary AIHA Steroids Splenectomy rituximab Azathioprine, MMF, High-dose cyclophosphamide, See text
cyclosporin, alemtuzumab
cyclophosphamide
B- and T-cell NHL Steroids Chemotherapy ⫾ rituximab 71,72
(splenectomy in SMZL)
Hodgkin lymphoma Steroids Chemotherapy 20
(radiotherapy)
Solid tumors Steroids, surgery 21
Ovarian dermoid cyst* Ovariectomy 22
MMF indicates mycophenolate mofetil; NHL, non-Hodgkin lymphoma; SMZL, splenic marginal zone lymphoma; SLE, systemic lupus erythematosus; SCT, stem cell
transplantation; CVID, common variable immunodeficiency; ALPD, autoimmune lymphoproliferative disease; and CAD, cold agglutinin disease.
*No personal experience.
†Off-label use.
retreatment with rituximab can be expected,51,52 but there are no study of Moyo et al,68 9 patients received several cycles of
data on the duration of a second remission. cyclophosphamide (50 mg/kg/d for 4 days) and 6 of 9 patients
Treatment options beyond second-line therapy. Immunosup- achieved a CR with a median duration of 15 months at the time of
pressive treatment was often recommended as preferred second- publication (2002). All of these patients are still in CR in 2010
line treatment because response rates of 40% to 60% have been (R.A. Brodsky, Sidney Kimmel Comprehensive Cancer Center at
claimed in earlier reviews.9,10,61 There is no doubt that immunosup- Johns Hopkins, Baltimore, MD, personal written communication,
pressive treatment is effective in some cases, but there is doubt on January 2010). The results of autologous stem cell transplantation
the overall efficacy. The opinion that cyclophosphamide is highly were disappointing.69 Alemtuzumab has been effective in a few
effective appears to be based on data from 2 earlier articles.62,63 patients, but toxicity is high.70
Those studies provided overall results but no specific patient On the basis of published data on benefits and risks (indepen-
details. A critical analysis of other published cases of patients dent of individual factors) in our opinion the sequence of second-
treated with azathioprine or cyclophosphamide39,41,64 shows that line treatments in primary WAIHA should be splenectomy, ritux-
probably fewer than one-third had any “response.” Many patients imab, and thereafter any of the immunosuppressive drugs (Figure
received concomitant treatment with steroids. The durability of 2). In practice the choice of the sequence mainly depends on the
responses is unknown in most studies. Dosing of azathioprine is personal experience of the physician, patient factors such as age
difficult because of the narrow therapeutic window, hypersensitiv-
and comorbidity, the availability and cost of drugs, and the
ity due to genetic defects, and interaction with other drugs.
preference of the patient. The main factor for the selection of any
Cyclophosphamide has a substantial mutagenic potential on long-
drug should be safety, because the curative potential of all these
term treatment. We regard the benefit/risk of azathioprine/cyclophospha-
drugs is low, and treatment may be more dangerous for the patient
mide only moderate at best. Skinner and Schwartz65 wrote on immuno-
than the disease to be treated.
suppressive drugs in AIHA in his review in 1972: “Unfortunately, all
that is known now is merely that immunosuppressive therapy of this
condition is feasible.” This is still true today. Treatment of secondary AIHA
All other immunosuppressive treatments (mycophenolate
mofetil, cyclosporine) have in common that only a very few WAIHA associated with systemic lupus erythematosus. Systemic
patients were treated, but, surprisingly, in almost all cases favorable lupus erythematosus is a most common cause of secondary AIHA
responses were achieved.66,67 This probably indicates that there was (Table 2). The preferred first-line therapies are steroids used in the
a strong selection bias. From the pretreatment data in rituximab same manner as in primary AIHA. The response rate is high. On a
trials it appears that, in the era before rituximab, azathioprine and maintenance treatment of 5 to 20 mg of PDN (in some patients with
cyclophosphamide were popular as second-line therapy, but we additional azathioprine or cyclophosphamide) the recurrence rate
have used immunosuppressants rarely because of doubts about was low (3-4/100 patient-years).81 The same second-line treat-
efficacy and the fear of side effects. ments as in primary AIHA have been effective in some cases.81
Treatment of last resort (severe anemia and none of the Rituximab has been effective in single cases, but there is a concern
known drugs have worked). High-dose cyclophosphamide has of an increased risk of PML in this particular disease. Splenectomy
been used as treatment for selected highly refractory patients. In the seems to have only a low long-term efficacy.
1836 LECHNER and JÄGER BLOOD, 16 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 11
Untreated drug-related AIHA, untreated AIHA in early stage CLL Steroids RCD 82,83
Untreated AIHA in active CLL Steroids ⫹ chlorambucil RCD; R-CVP 16,84,85
Steroid-refractory, nonprogressive CLL Rituximab; cyclosporin; splenectomy RCD; R-CVP 86-88
Multiply refractory AIHA, advanced or progressive CLL Alemtuzumab 89
RCD indicates rituximab, cyclophosphamide, and dexamethasone; and R-CVP, rituximab, cyclophosphamide, vincristine, prednisone.
AIHA associated with malignancies Primary chronic cold agglutinin disease. Primary cold agglu-
tinin disease (CAD) is defined as a CAIHA in patients with
CLL-associated WAIHA. For the treatment of patients with IgM–monoclonal gammopathy of undetermined significance or in
recruit enough patients. A solution could be a cooperative world- thank R.A. Brodsky, C.L. Bennett, and R.W. Thomsen for provid-
wide effort of hematologists to set up a registry of patients with ing additional information on their patients (studies). We thank
AIHA who had undergone splenectomy or rituximab treatment for Hanna Obermeier and Michaela Bronhagl for secretarial assistance.
retrospective analysis of these cases. The results would of course
not be evidence-based medicine of highest standard, but certainly
they would much better than the current state of knowledge. These Authorship
data could be the basis for future prospective comparative studies
with known or new drugs.97 Contribution: K.L. and U.J. retrieved data and wrote the paper.
Conflict-of-interest disclosure: K.L. has received a lecture fee
from Hoffmann-La Roche. U.J. has received research support and
Acknowledgments lecture fees from Hoffmann-La Roche.
References
1. Klein NP, Ray P, Carpenter D, et al. Rates of au- 19. Gertz MA. Cold hemolytic syndrome. Hematology 33. Petz LD. “Least incompatible” units for transfu-
toimmune diseases in Kaiser Permanente for use Am Soc Hematol Educ Program. 2006;19-23. sion in autoimmune hemolytic anemia: should we
in vaccine adverse event safety studies. Vaccine. 20. Lechner K, Chen YA. Paraneoplastic autoimmune eliminate this meaningless term? A commentary
2010;28(4):1062-1068. cytopenias in Hodgkin lymphoma. Leuk Lym- for clinicians and transfusion medicine profes-
2. Eaton WW, Rose NR, Kalaydjian A, Pedersen phoma. 2010;51(3):469-474. sionals. Transfusion. 2003;43(11):1503-1507.
MG, Mortensen PB. Epidemiology of autoimmune 21. Puthenparambil J, Lechner K, Kornek G. Autoim- 34. Ruivard M, Tournilhac O, Montel S, et al. Plasma
diseases in Denmark. J Autoimmun. 2007;29(1): mune hemolytic anemia as a paraneoplastic phe- exchanges do not increase red blood cell transfu-
1-9. nomenon in solid tumors. A critical analysis of 52 sion efficiency in severe autoimmune hemolytic
3. Pirofsky B. Clinical aspects of autoimmune hemo- cases reported in literature. Wien Klin Wochen- anemia: a retrospective case-control study. J Clin
lytic anemia. Semin Hematol. 1976;13(4):251- schr. 2010;122:229-236. Apher. 2006;21(3):202-206.
265. 22. Payne D, Muss HB, Homesley HD, Jobson VW, 35. Nakasone H, Kako S, Endo H, et al. Diabetes
4. Sokol RJ, Hewitt S, Stamps BK. Autoimmune Baird FG. Autoimmune hemolytic anemia and mellitus is associated with high early-mortality
haemolysis: an 18-year study of 865 cases re- ovarian dermoid cysts: case report and review of and poor prognosis in patients with autoimmune
ferred to a regional transfusion centre. Br Med J the literature. Cancer. 1981;48(3):721-724. hemolytic anemia. Hematology. 2009;14(6):361-
(Clin Res Ed). 1981;282(6281):2023-2027. 365.
23. Jeffries M, Hamadeh F, Aberle T, et al. Haemolytic
5. Engelfriet CP, Overbeeke MA, von dem Borne anaemia in a multi-ethnic cohort of lupus patients: 36. Hendrick AM. Auto-immune haemolytic anae-
AE. Autoimmune hemolytic anemia. Semin a clinical and serological perspective. Lupus. mia–a high-risk disorder for thromboembolism?
Hematol. 1992;29(1):3-12. 2008;17(8):739-743. Hematology. 2003;8(1):53-56.
6. Dacie SJ. The immune haemolytic anaemias: a 24. Giannadaki E, Potamianos S, Roussomoustakaki 37. Pullarkat V, Ngo M, Iqbal S, Espina B, Liebman
century of exciting progress in understanding. M, Kyriakou D, Fragkiadakis N, Manousos ON. HA. Detection of lupus anticoagulant identifies
Br J Haematol. 2001;114(4):770-785. Autoimmune hemolytic anemia and positive patients with autoimmune haemolytic anaemia at
Coombs test associated with ulcerative colitis. increased risk for venous thromboembolism. Br J
7. Garratty G. The James Blundell Award Lecture
Am J Gastroenterol. 1997;92(10):1872-1874. Haematol. 2002;118(4):1166-1169.
2007: Do we really understand immune red cell
destruction? Transfus Med. 2008;18(6):321-334. 25. Sève P, Bourdillon L, Sarrot-Reynauld F, et al. 38. Allgood JW, Chaplin H Jr. Idiopathic acquired au-
DEF-I Study Group. Autoimmune hemolytic ane- toimmune hemolytic anemia. A review of forty-
8. Petz LD. Cold antibody autoimmune hemolytic seven cases treated from 1955 through 1965.
anemias. Blood Rev. 2008;22(1):1-15. mia and common variable immunodeficiency: a
case-control study of 18 patients. Medicine (Balti- Am J Med. 1967;43(2):254-273.
9. Murphy S, LoBuglio AF. Drug therapy of autoim- 39. Serrano J. Autoimmune hemolytic anemia. Re-
more). 2008;87(3):177-184.
mune hemolytic anemia. Semin Hematol. 1976; view of 200 cases studied in a period of 20 years
13(4):323-334. 26. Straus SE, Sneller M, Lenardo MJ, Puck JM,
Strober W. An inherited disorder of lymphocyte (1970-1989). Sangre (Barc). 1992;37(4):265-274.
10. Gehrs BC, Friedberg RC. Autoimmune hemolytic 40. Chertkow G, Dacie JV. Results of splenectomy in
apoptosis: the autoimmune lymphoproliferative
anemia. Am J Hematol. 2002;69(4):258-271. auto-immune haemolytic anaemia. Br J Haema-
syndrome. Ann Intern Med. 1999;130(7):591-601.
11. Gertz MA. Management of cold haemolytic syn- tol. 1956;2(3):237-249.
27. Sanz J, Arriaga F, Montesinos P, et al. Autoim-
drome. Br J Haematol. 2007;138(4):422-429. 41. Genty I, Michel M, Hermine O, Schaeffer A,
mune hemolytic anemia following allogeneic he-
12. King KE, Ness PM. Treatment of autoimmune matopoietic stem cell transplantation in adult pa- Godeau B, Rochant H. Characteristics of autoim-
hemolytic anemia. Semin Hematol. 2005;42(3): tients. Bone Marrow Transplant. 2007;39(9):555- mune hemolytic anemia in adults: retrospective
131-136. 561. analysis of 83 cases. Rev Med Interne. 2002;23(11):
13. Packman CH. Hemolytic anemia due to warm 901-909.
28. Elimelakh M, Dayton V, Park KS, et al. Red cell
autoantibodies. Blood Rev. 2008;22(1):17-31. aplasia and autoimmune hemolytic anemia fol- 42. Akpek G, McAneny D, Weintraub L. Comparative
14. Michel M. Characteristics of warm autoimmune lowing immunosuppression with alemtuzumab, response to splenectomy in Coombs-positive au-
hemolytic anemia and Evans syndrome in adults. mycophenolate, and daclizumab in pancreas toimmune hemolytic anemia with or without asso-
Presse Med. 2008;37(9):1309-1318. transplant recipients. Haematologica. 2007;92(8): ciated disease. Am J Hematol. 1999;61(2):98-102.
15. Valent P, Lechner K. Diagnosis and treatment of 1029-1036. 43. Coon WW. Splenectomy in the treatment of he-
autoimmune haemolytic anaemias in adults: a 29. Dearden C. Disease-specific complications of molytic anemia. Arch Surg. 1985;120(5):625-628.
clinical review. Wien Klin Wochenschr. 2008; chronic lymphocytic leukemia. Hematology Am 44. Casaccia M, Torelli P, Squarcia S, et al. Laparo-
120(5-6):136-151. Soc Hematol Educ Program. 2008;450-456. scopic splenectomy for hematologic diseases: a
16. Mauro FR, Foa R, Cerretti R, et al. Autoimmune 30. Chiao EY, Engels EA, Kramer JR, et al. Risk of preliminary analysis performed on the Italian
hemolytic anemia in chronic lymphocytic leuke- immune thrombocytopenic purpura and autoim- Registry of Laparoscopic Surgery of the Spleen
mia: clinical, therapeutic, and prognostic features. mune hemolytic anemia among 120 908 US vet- (IRLSS). Surg Endosc. 2006;20(8):1214-1220.
Blood. 2000;95(9):2786-2792. erans with hepatitis C virus infection. Arch Intern 45. Thomsen RW, Schoonen WM, Farkas DK, et al.
17. Zent CS, Ding W, Reinalda MS, et al. Autoim- Med. 2009;169(4):357-363. Risk for hospital contact with infection in patients
mune cytopenia in chronic lymphocytic leukemia/ 31. Hoffman PC. Immune hemolytic anemia–selected with splenectomy: a population-based cohort
small lymphocytic lymphoma: changes in clinical topics. Hematology Am Soc Hematol Educ Pro- study. Ann Intern Med. 2009;151(8):546-555.
presentation and prognosis. Leuk Lymphoma. gram. 2009;80-86. 46. Yong M, Thomsen RW, Schoonen WM, et al.
2009;50(8):1261-1268. 32. Arndt PA, Leger RM, Garratty G. Serologic find- Mortality risk in splenectomised patients: a Dan-
18. Grønbaek K, D’Amore F, Schmidt K. Autoimmune ings in autoimmune hemolytic anemia associated ish population-based cohort study. Eur J Intern
phenomena in non-Hodgkin’s lymphoma. Leuk with immunoglobulin M warm autoantibodies. Med. 2010;21(1):12-16.
Lymphoma. 1995;18(3-4):311-316. Transfusion. 2009;49(2):235-242. 47. Ejstrud P, Kristensen B, Hansen JB, Madsen KM,
1838 LECHNER and JÄGER BLOOD, 16 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 11
Schønheyder HC, Sørensen HT. Risk and patterns Dacie JV. Immmunosuppressive drugs in the mune anaemias in patients with chronic lympho-
of bacteraemia after splenectomy: a population- treatment of autoimmune haemolytic anaemia. cytic leukaemia treated with fludarabine, cyclo-
based study. Scand J Infect Dis. 2000;32(5):521- Proc R Soc Med. 1968;61(12):1312-1315. phosphamide and rituximab–incidence and
525. 65. Skinner MD, Schwartz RS. Immunosuppressive predictors. Br J Haematol. 2007;136(6):800-805.
48. Thomsen RW, Schoonen WM, Farkas DK, Riis A, therapy, 1. N Engl J Med. 1972;287(5):221-227. 83. Hallek M, Cheson BD, Catovsky D, et al. Interna-
Fryzek JP, Sørensen HT. Risk of venous throm- 66. Kotb R, Pinganaud C, Trichet C, et al. Efficacy of tional Workshop on Chronic Lymphocytic Leuke-
boembolism in splenectomized patients com- mycophenolate mofetil in adult refractory auto- mia. Guidelines for the diagnosis and treatment
pared with the general population and appendec- immune cytopenias: a single center preliminary of chronic lymphocytic leukemia: a report from
tomized patients: a 10-year nationwide cohort study. Eur J Haematol. 2005;75(1):60-64. the International Workshop on Chronic Lympho-
study [letter]. J Thromb Haemost. Prepublished cytic Leukemia updating the National Cancer
67. Emilia G, Messora C, Longo G, Bertesi M. Long-
on March 9, 2010, as DOI 10.1111/j.1538- Institute-Working Group 1996 guidelines. Blood.
term salvage treatment by cyclosporin in refrac-
7836.2010.03849. 2008;111(12):5446-5456.
tory autoimmune haematological disorders. Br J
49. Parker AC, MacPherson AI, Richmond J. Value of Haematol. 1996;93(2):341-344. 84. Kaufman M, Limaye SA, Driscoll N, et al. A com-
radiochromium investigation in autoimmune hae- bination of rituximab, cyclophosphamide and
68. Moyo VM, Smith D, Brodsky I, Crilley P, Jones